2beta,3beta - alkylindenedioxy - 6 - oxygenation bis nor cholanic acid compounds and the methyl esters thereof



United States Patent 3,547,910 2,8,35 ALKYLINDENEDIOXY 6 OXYGENATION BISNOR CHOLANIC ACID COMPOUNDS AND THE METHYL ESTERS THEREOF Andor Fiirstand Andr Furlenmeier, Basel, Albert Langemann, Binningen, and GuyWaldvogel, Riehen, Switzerland, and Peter Hocks, Ulrich Kerb, and RudolfWiechert, Berlin, Germany, assignors to Hotfmann-La Roche Inc., Nutley,N.J., a corporation of New Jersey No Drawing. Original application Aug.9, 1966, Ser. No. 571,187. Divided and this application Feb. 29, 1968,Ser. No. 709,187 Claims priority, application Germany, Oct. 15, 1965,

Sch 37,892; Jan. 27, 1966, Sch 38,384; Switzerland, Mar. 24, 1966,4,336/ 66 Int. Cl. C07c 173/00 US. Cl. 260-23955 Claims ABSTRACT OF THEDISCLOSURE This invention is directed to 22-functionalized2,3-disubstituted 6-keto steroids which are useful as metamorphosishormones and are additionally useful as intermediates for the productionof other insect hormones. Accordingly, the compounds may be employed inthe control of insect population.

[RELATED APPLICATIONS This application is a division of applicantscopending application Ser. No. 571,187, filed Aug. 9, 1966 nowabandoned. Other related applications of Ser. No. 571,187, filed by theapplicants include Process for the Preparation of 5fi H-6-Keto-Steroids,Ser. No. 709,238, filed of even date herewith;5/3-H-6-Keto-Pregnane-Derivatives, Ser. No. 709,186, filed of even dateherewith and -Hydrocarbyl-6-Keto-Steroids, Ser. No. 709,239, filed ofeven date herewith.

DETAILED DESCRIPTION OF THE INVENTION This invention is concerned withsteroids having activities as insect metamorphosis hormones and tomethods for their production. This invention is also concerned withcertain novel steroids which are useful per se as metamorphosis hormonesand are additionally useful as intermediates for the production of otherinsect metamorphosis hormones.

The steroids which are produced in accordance with the processes of thisinvention are those represented by the formula:

wherein -R is hydrogen or methyl; R is hydrogen, hydroxy, lower acyloxy,or lower alkoxy; R is hydroxy, lower acyloxy, or lower alkoxy; R and Rwhen taken together and when [R is in the ,B-orientation, are loweralkylenedioxy; A represents a single or a double bond; R is hydrogen orhydroxy; R is hydrogen or lower alkyl; R, when R is lower alkyl, ishydroxy or lower acyloxy,

and when R is hydrogen, is hydroxy, lower acyloxy, or a radical of theformula C(CH )R R R when taken alone, is hydrogen or hydroxy; R whentaken alone, is CO Z, CHO, CH(O-lower alkyl) cHz c OzZ aliphatichydrocarbyl or aliphatic hydrocarbyl substituted with up to 2substituents of the group consisting of hydroxy, lower acyloxy, loweralkoxy, or tetrahydropyranyloxy; R and :R when taken together, are oxo;and Z is hydrogen or lower alkyl.

By the term lower acyloxy is meant a radical derived from an aliphaticcarboxylic acid of up to about 11 carbons by removal of the hydrogen ofthe carboxyl group. The acid may be saturated or unsaturated, straightor branched chain, and may contain one or more substituents, such ashalo, including chloro and fluoro, nitro, oxy, and the like. Suitableacids include formic acid, acetic acid, propionic acid, trimethylaceticacid, caproic acid, enanthic acid, hendeanoic acid, phenylacetic acidbenzoi acid, cyclopentylpropionic acid, trifluoroacetic acid,aminoacetic acid, oxypropionic acid, adipic acid, and the like.Preferred are hydrocarbyl acyclic mono-basic acids of up to about 6carbons, with alkanoic monocarboxylic acids being especially preferred.

By the terms lower alkyl and lower alkoxy are meant alkyl and alkoxygroups of up to about 6 carbons, such as methyl, ethyl, propyl,isopropyl, butyl, tert.- butyl, hexyl, mcthoxy, ethoxy, tert.-butoxy,and the like.

By the term lower alkylenedioxy group is meant a divalent radical of theformula -OR O-, wherein R is an alkylene, Le, a divalent saturatedacyclic hydrocarbon, radical of up to about 10 carbons, and preferablyup to about 6 carbons. Especially preferred are alkylidenedioxy groups,with isopropylidenedioxy being most preferred.

By the term aliphatic hydrocarbyl group is meant a monovalent radicalfree of aromatic unsaturation and consisting of carbon and hydrogen,such as alkyl, alkenyl, alkynyl, alkadienyl, and the like, and may beeither branched or straight chain. Preferred aliphatic hydrocarbylgroups are alkyl groups and al kynyl groups of up to about 6 carbons,such as ethynyl, propyl, isopropyl, butyl, isobutyl, butynyl, pentyl,isopentynyl, and the like, with branched-chain groups being preferred.Preferred substituted aliphatic hydrocarbyl groups are those representedby the formula -CH(OH) R wherein R is aliphatic hydrocarbyl of up toabout 5 carbons, preferably branched chain, and especially branchedalkyl or alknyl, which may be substituted with a hydroxy group, a loweralkyl group, a lower alkoxy group, or a tetrahydropyranyl group.

The novel products of this invention are illustrated by the followingformulae:

34 CH? R3 II I wherein:

R and R are as defined above;

R and R each when taken alone, is hydroxy, lower acyloxy, or loweralkoxy, and R and R can be the same or different;

R and R when taken together, and R is in the ,B-orientation, are loweralkylenedioxy;

A is as defined above;

R is hydrogen or lower alkyl;

R when R is lower alkyl, is hydroxy or lower acyloxy, and when R ishydrogen, is hydrogen, lower acyloxy, or a radical of the formula -C(CH)R R R when taken alone, is hydrogen or hydroxy;

R when taken alone, is CO Z, CHO,

CHtO-lower alkyl) \CH2/2 COzZ aliphatic hydrocarbyl, or aliphatichydrocarbyl substituted with up to two substituents of the groupconsisting of hydroxy, lower acyloxy, lower alkoxy, ortetrahydropyranyloxy;

R when taken alone, and When R is hydrogen, is

CO Z, CHO, CHt-O-lower alkyl) \CHz/2 COzl or aliphatic hydrocarbyl, andwhen R is hydroxy, is R R and R when taken together, are oxo;

R and R", when taken together, are oxo;

Z is hydrogen or lower alkyl;

R when A represents a single bond, is hydrogen, and

when A represents a double bond, is hydrogen or hydroxy;

Y is hydrogen, lower alkyl, or lower acyl; and

R is aliphatic hydrocarbyl or aliphatic hydrocarbyl substituted with upto one substituent of the group consisting of hydroxy, lower acyloxy,lower .alkoxy, or tetrahydropyranyloxy.

An especially preferred class of compounds of this invention are thosedefined by the formula:

wherein R R R A, and Z are as defined above.

It is also within the contemplation of the present invention that thesteroids of Formulae I-VI may have substituents or unsaturatedcarbon-carbon bonds other than those specifically depicted. For example,a lower alkyl group may be present on the 1-, 7-, or 16-positions, ahydroxy or lower acyloxy group may be present in the 1-, 11-, 16-, or17-positions, and double bonds may be present in the 1(2)- and/or the3(4)-positions.

The production of Sfl-H-steroids of the type defined by Formulae II,III, and VI is unexpected in view of the teachings of A. Schubert, J.Org. Chem., 26, 159 (1964); H. B. Henbest, J. Chem. Soc., 1967, 4596 and4765; and N. L. Allenger, J. Org. Chem, 26, 3626 (1961). Thesepublications disclose that 5fl-H-6-ketosteroids which are unsubstitutedin the 2-position are isomerized under acidic or basic conditions to thecorresponding 5a-H-steroids, thus leading to the conclusion that theA/B-trans-ring linkage is the more stable form for 6-ketosteroids.Unexpectedly, it has been discovered by this invention that 6-ketosteroids substituted in both the 2- and 3-positions with hydroxygroups or esterified or etherified hydroxy groups and having anA/B-cis-ring linkage are stable.

The various products of this invention are obtained by both known andnovel reactions from known starting materials such as A-cholesten-6-one, methyl 3,3-ethylenedioxy A pregnen 20 carboxylate, 3hydroxy A cholesten 6 one, 3 acetoxy A 22 ergostadien 6- one, 3a hydroxy20,20 ethylenedioxy 5a H pregnan 6 one,- 3,3 ethylenedioxy 2Ohydroxymethyl- A -pregnen, and the like.

A major novel reaction employed in producing the products of thisinvention comprises the conversion of a 2B,3dihydroxy-Sa-H-6-ketosteroidor a monoor diester or monoor diether thereof to the corresponding 55-H-compound; i.e., by elfecting isomerization at the 5-position, as isillustrated by Equation A, employing partial formulas for startingmaterial and product:

Equation A CH: CH:

n H H II wherein B represents the remainder of the steroid nucleus, Thisprocess is particularly useful for producing a compound of Formula IIabove from the corresponding Set-H- steroid.

The isomerization is effected by the introduction of energy such as bythermal energy, irradiation, and the like, preferably in the presence ofan inert organic solvent, Suitable solvents include alcohols such asmethanol and ethanol; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, and dioxane; ketones such as acetone and methyl ethylketone; esters such as ethyl acetate; hydrocarbons such as benzene;chlorinated hydrocarbons such as chloroform; and the like.

The introduction of thermal energy is effected by heating at elevatedtemperatures, such as at about 50 C. or higher, and preferably in therange of from about 60 to about 80 C. The presence of acidic or basiccatalysts, heretofore known as isomerization catalysts, promotes therate of isomerization and permits the use of lower temperatures.Suitable acid catalysts include sulfuric acid, perchloric acid, selenousacid, p-toluene-sulfonic acid, and Lewis acids such as borontrifluoride, magnesium bromide, mercury chloride, aluminum chloride, andthe like. Basic catalysts which can be employed include inorganic basessuch as alkali metal hydroxides, for example, sodium hydroxide orpotassium hydroxide, and alkaline earth metal hydroxides, for example,calcium hydroxide or magnesium hydroxide; as well as basic salts such aspotassium carbonate, and the like; and organic bases such astriethylamine, benzltrimethylammonium hydroxide, pyridine, or lutidine.In addition, acidic or basic adsorption agents such as aluminum oxide orsilica gel will also catalyze the isomerization.

The acidic or basic reaction medium, in addition to catalyzing theisomerization at the 5-position, can also be employed to promote otherstructural changts in the steroid. For example, selenium dioxide(selenols acid), which is employed to introduce a hydroxy group in the Ila-position, as hereinafter described, is sufficiently acidic to effectisomerization of the Set-hydrogen to the 5,8- hydrogen.

The temperature and reaction time necessary to achieve the isomerizationwill vary depending upon the catalyst, but suitable temperatures andtimes can be readily determined by those having ordinary skill in theart. For example, at 60-80 C. times of about 4 hours are normallyemployed when hydrochloric acid is employed as the catalyst, whereasabout 1 hour is sufiicient when potassium hydroxide is employed. On theother hand, isomerization occurs at C. in less than 1 hour when borontrifluoride is the catalyst.

The isomerization of this invention may also be effected by the use ofultraviolet radiation, by which term is meant light having a wave lengthof less than about 4000 Angstrom units.

The product of the isomerization, if conducted for a sufiicient lengthof time, is an equilibrium mixture of the Su-H- and B-H-isomers inapproximately equirnolar amounts. At short times and/ or with weakcatalysts, less than an equimolar ratio of SB-H- to 5a-H-steroid isproduced. These isomers may be separated, however, by techniques knownto the art such as chromatography, fractional crystallization, and thelike. In addition, when the isomerization product is a 25,3,8-dihydroxycompound, the isomers may be separated by reaction with aceticanhydride. The SB-H-isorner readily forms a 213,3B-acetate, whereas the5 a-H-isomer forms a 2fl-hydroxy-3B-acetate. The diacetate is normallyless soluble than the monoacetate and thus can be readily precipitatedfrom the reaction mixture. The 5a-H-monoacetate, which remains insolution, can then be subjected to a second isomerization in accordancewith this invention.

The products of this process can be hydrolyzed or acylated, if desired,by known reaction techniques. Fur thermore, compounds wherein R and Rwhen taken together are alkylenedioxy, are readily formed by theacidcatalyzed reaction of a 213,313-dihydroxy compound with a ketone,for example, acetone.

A second novel reaction of this invention, and one which is related tothe above-described isomerization, comprises the conversion of a2fl,3fi-dihydroxy-5a-H-6- keto-N-steroid which is unsubstituted in the14-position or a monoor diether or mono or diester thereof to thecorresponding 5fl-H-14or-hydroxysteroid, as is illustrated by EquationB:

This reaction is effected by the use of selenium dioxide, and isnormally conducted in an inert solvent such as those discussed above.The reaction temperature is not narrowly critical, although elevatedtemperatures, preferably of from about 50 to about C., are normallyemployed. The product 5B-H-14m-hydroxysteroid is recovered from thereaction medium by conventional techniques.

Still another novel technique for producing25,3-dihydroxy-SB-H-6-ketosteroids or mono or diethers or monoordiesters thereof comprises the acid-catalyzed isomerization of acorresponding 5,6-oxidesteroid, as is illustrated by Equation C:

The oxirane ring of the starting material of this process may be ineither the OL- or fi orientation. Suitable acid catalysts are thosediscussed above with reference to the stZ-H- to SB-H-isomerization. Thisreaction is normally effected in the presence of an inert organicsolvent such as those discussed above. The reaction temperature is notnarrowly critical, although it is preferred to employ realtively lowtemperatures, especially those in the range of from about -10 C. toabout +30 C.

Still another novel transformation useful in producing a25,3fl-dihydroxy-5fi-H-6-ketosteroid is that proceeding from a3,6-dioxo-5a-H-steroid by a series of reactions illustrated by EquationsD, E, and F, employing partial formulas:

The reaction steps outlined above are novel and yield unexpected resultsboth individually and in combination. This sequence is especiallyvaluable for producing compounds of Formula'II wherein A represents asingle bond.

In the first step of this reaction sequence (Equation D), a3,6-dioxo-a-H-steroid is brominated by generally known techniques toproduce a 2oc-bIOmO-3,6-dlOXO-5oc- H-steroid. This result is unexpectedin view of the disclosure of L. H. Sarett, J. Org. Chem. 8, 405 (1943)that the bromination of 3,6-cholanedione, a Sfl-H-steroid, yields amixture of polybromo compounds.

The bromination of this invention is effected by reacting the3,6-diketosteroid with bromine in any suitable manner. A preferredprocedure comprises dissolving the 3,6-ketosteroid in a solvent which isinert towards bromine, such as tetrahydrofuran, dioxane, ether, benzene,

or chloroform, and subsequently adding to this solution a solution ofbromine in acetic acid dropwise at reduced temperature, i.e., belowabout room temperature C.). On completion of the bromination, freehydrogen bromide produced by the reaction is neutralized, as by theaddition of a buffer such as potassium acetate.

In the second step of this novel reaction sequence (Equation E), the3-keto group of the 2u-bromo-3,6- diketosteroid is selectively reducedby reaction of the steroid with a lithium tri(lower alkoxy)aluminumhydride, preferably a lithium tri(tert.-lower alkoxy)aluminum hydride,such as lithium tri(tert.-butoxy)aluminum hydride or lithiumtri(tert.-amyloxy)aluminum hydride. This reduction is effected in aninert organic solvent such as dioxane, tetrahydrofuran, or ether, and ispreferably effected at reduced temperatures, especially in the range offrom about 5 to about +15 C. The production of a3,8-hydroxy-6-ketosteroid in this manner is entirely unexpected, for itcould not be foreseen that the 3,6-diketo system would be susceptible toselective reduction. Furthermore, if one were to predict which of thetwo keto groups a,

would be more likely to be reduced, the free-standing 6-keto group wouldappear to be the most susceptible to preferential reduction. This isbecause attack at the 3-keto group by the bulky lithium tri(loweralkoxy)aluminum hydride compounds would be expected to be stericallyhindered by the 2a-bromo atom.

The final reaction step of this sequence (Equation F) comprises thereplacement of the 2a-bromo atom with a 2,8-acyloxy group, employinggenerally known techniques but leading to the unexpected SB-H-steroids.In a preferred technique, the 2a-bromo3fi-hydroxysteroid produced by theabove-described selective reduction is esterified to form a 2a-bromo-38-acyloxysteroid, which is then reacted with an alkali metal acylate ora silver acylate, preferably an acetate, and most desirably silveracetate. This reaction is normally effected at elevated temperatures,preferably in the range of from about 75 C. to about 125 C. As with thepreviously described Sa-H- to Sfl-H-isomerization, the product of thisreaction is a mixture of cand 5 8-H-isomers, which may be readilyseparated by known techniques.

A further novel reaction sequence of this invention comprises theconversion of a 2,6,3B-dihydroxy-6-keto-A pregnen-ZO-carboxylic acid tothe corresponding aldehyde, as is illustrated by Equation G:

8 EQUATION G CH COZH CH3 CH0 \f 1130 I Hi R Rl I I R2 2 H [I H H Thisconversion is effected by first reacting the acid, the hydroxy groups ofwhich are preferably protected, as by conversion to acyloxy, alkoxy, oralkylenedioxy groups, with carbonyl diimidazole in accordance with knownprocedures to form an imidazolide. This product is then reacted with alithium tri(lower alkoxy)aluminum hydride to effect selective conversionof the imidazolide group to the formyl group. This reaction isunexpected because the normally used reducing agent, lithium aluminumhydride, is known to effect reduction of keto groups and elimination ofester groups. The reaction is preferably conducted in the absence offree oxygen, as in an argon or nitrogen atmosphere. The reactiontemperature is not narrowly critical, although temperatures of aboutroom temperature (20-25 C.) are normally employed. The reaction isgenerally effected in the presence of an inert organic solvent such asthose previously discussed above.

A final novel process of the present invention comprises the conversionof a 20-formylpregnan-6-one to a20-(l-hydroxy-hydrocarbyl)-pregnan-6-one, as is illustrated by EquationH:

This reaction is effected by reacting the 20-formyl compound with aGrignard reagent having the formula:

R MgX wherein R is as defined above and X is chlorino, bromine, oriodine. This conversion is effected in the presence of an inert solventsuch as those previously disclosed and preferably an ether such astetrahydrofuran, ether, dioxane, or the like. The temperature ofv thereaction is not narrowly critical, but reduced temperatures, preferablyin the range of from about 5 C. to about +15 C. and more especiallyabout 0-5 C., are employed to ensure as quantitative and selective areaction as possible.

In a preferred technique, a solution of the Grignard reagent is slowlyadded with stirring to a solution of the 20-formyl compound. Theselective reaction with the 20- formyl group without attack on the6-keto group or an acyl group is unexpected, for it is well known thatGrignard reagents readily react With such groups. The reaction time isnot narrowly critical, and the reaction is generally complete afterabout to minutes under the foregoing conditions. However, the reactionperiod can be permitted to extend as long as about 30 or even about 60minutes without the occurrence of significant side reactions.

When R is an unsaturated group, the unsaturated side chain may beselectively hydrogenated over a metal catalyst, such as palladium, andpreferably platinum dioxide, employed as such or deposited onconventional supports. The hydrogenation is preferably eifected in asolvent for the steroid such as a lower alcohol, for example, methanolor ethanol; an ether, for example, diethyl ether, dioxane, ortetrahydrofuran; an ester, for example, ethyl acetate; or a hydrocarbon,for example, benzene. Carboxylic acids, such as acetic acid, are notdesirable because they promote the reduction of the 6-keto group as wellas the N-bond, if present.

When a 14a-hydroxy compound is desired as the prodnet, the hydrogenationshould be effected prior to the introduction of the 14rx-hydroxy groupbecause of the tendency of the hydrogenation to effect at least partialelimination of this group. Alternatively, the Grignard reaction may beeffected with a reagent wherein R is already saturated.

The 14u-hydroxylation may be effected by known techniques, as well as bythe previously described reaction with selenous acid, which may beeffected with either a Soc-H- or a SQ-H-steroid. Additionally,14a-hydroxylation may be effected by biochemical methods, as by theaction of microorganisms and/or the enzymes formed by them. Suitablesystems include enzymes of the type Curvularia, preferably Curvularialunata, the type Absidia, preferably Absidia regnieri, and especially ofthe type Heliocostylum, preferably Heliocostylum piriforme, or the typeMucor, preferably Mucor gl'iseowyanus.

As indicated above, the various products of this invention possessactivity as insect metamorphosis hormones. Thus, the products of thisinvention may be employed to induce insect metamorphosis at a point intime which is detrimental to the further population of the insect.Because of the hormonal nature of these products, a resistance to theiraction cannot develop, thus avoiding a significant disadvantage ofconventional insecticides. In addition to their metamorphosis-inducingactivity, the products of this invention possess a profound influence onthe cell metabolism in other animals, especially in warm-blooded animalsor crustaceans. For example, by the use of the products of thisinvention, it is possible to induce the moulting stage in crustaceans,thus rendering them suitable as fish bait. Additionally, the products ofthis invention can be employed to control crustacean infestation and thedamage caused thereby by inducing the moulting stage and exposing thecrustacean to natural decimation. Furthermore, the products of thisinvention have been observed to have central nervous system activity. Itis thus readily apparent that the products of this invention have wideutility as pharmaceuticals in hormone and veterinary medicine as well asuse as agents for the control of insects in agricultural applications.Furthermore, many of the products of this invention serve asintermediates for the manufacture of still other valuable medicinal oragricultural agents.

The products of this invention can be employed in the form ofpreparations which contain them in admixture with suitable organic orinorganic inert carrier materials such as, for example, water, starch,magnesium stearate, talc, vegetable oils, polyalkylene glycol, or thelike.

The following examples are illustrative. For convenience in followingthe reaction sequences employed, each example is limited to theproduction of derivatives of a single known starting material, but mayillustrate the production of several of the products of this inventionas well as the use of one or more of the novel processes of thisinvention. It is to be understood, however, that these examples are notlimited to the specific starting materials or sequences employed, andthat other starting materials and reactions known to the art may be usedwhere desired.

EXAMPLE I.-FROM A -CHOLESTEN-6-ONE (A) Synthesis of2,8-acetoxy-3B-hydroxy-h-cholestan-6- one To a solution of 2 grams of5a-A -cholesten-6-one in 270 milliliters of glacial acetic acid and 3.7milliliters of water, there was added 3.2 grams of silver acetate and,with intensive stirring, 1.9 grams of iodine. The resulting reactionmixture was heated with stirring at 45 C. for 3 hours, treated with anexcess of common salt, stirred for an additional 5 minutes, and thenfiltered. The deep red filtrate was then evaporated to dryness undervacuum and the residue was taken up in ethyl acetate, washed in sequencewith water, thiosulfate solution, and again with water, dried oversodium sulfate, and concentrated to obtain25-acetoxy-3B-hydroxy-5a-cholestan-6-one, melting point 217-218 C. (frommethylene chloride/acetonitrile).

(B) Synthesis of 25,3,B-dihydroxy-5a-cholestan-6-one An admixture of 2.2grams of 2fl-acetoxy-3fl-hydroxy- 5a-cholestan-6-one and 1.1 grams ofpotassium carbonate in 200 milliliters of absolute methanol was stirredat room temperature for hours. The reaction solution was thereafterconcentrated in vacuum. The residue, after being taken up in ethylacetate, was washed with water, thiosulfate solution, and again withwater, dried, and concentrated to obtain2/3,3B-dihydroxy-Sa-cholestan-6-one, melting point 212213 C. (fromacetonitrile).

(C) Synthesis of 25,35-diacetoxyand 2 3,3,B-dihydroxy-5/3-cholestan-6-one (1) FROM 25,3 3-DIHYDROXY-5a.CHOLESTAN B-ONE (a)Acid-catalyzed reaction.A solution of 500 milligrams of2,8,35-dihydroxy-5a-cholestan-fi-one in milliliters of ethanol and 5milliliters of 3 N hydrochloric acid was heated at boiling for 4 hours.After cooling and dilution with water, the reaction solution wasextracted with chloroform. The extract was washed with water, dried oversodium sulfate and concentrated in vacuum to yield2p,3B-dihydroxycholestan-6-one as an approximately equimolar mixture ofthe Su-H- and SB-H-isomers.

(b) Base-catalyzed reaction.A mixture of 600 milligrams of2B,3,8-dihydroxy-5a-cholestan-6-one, 500 milligrams of potassiumhydroxide .and 10 milliliters of methanol was heated at reflux for onehour. After cooling, the reaction mixture was treated with water andextracted with chloroform. After workup of the extract, there wasobtained 2e,3,8-dihydroxycholestan-6-one as an approximately equimolarmixture of the Sa-H- and 5 3-H-isomers.

(a) Acid-catalyzed reaction.A solution of 1 gram of2B-acetoxy-3fl-hydroxy-Sa-cholestan-6-one in milliliters of ethanol and10 milliliters of 3 N hydrochloric acid was heated at reflux for 4hours. After cooling, the reaction mixture wa diluted with water andextracted with ethyl acetate. The extract was worked up to yield 213,33- dihydroxycholestan-G-one as an approximately equimolar mixture of theSoc-H- and Sfl-H-isorners.

(b) Base-catalyzed reaction.A mixture of 1 gram of2fl-acetoxy-3/3-hydroxy-5a-cholestan-6-one and 1 gram of potassiumhydroxide in 20 milliliters of methanol was heated at reflux for 2hours. After cooling, the reaction mixture was diluted with water andextracted with ethyl acetate. After workup of the extract, there wasobtained 23,3;3-dihydroxy cholestan 6 one as an approximately equimolarmixture of the Soc-H- and SB-H-isomers.

A solution of 1 gram of 2,8,3/3-dihydroxycholestan-6- one--H-isomericmixture produced as described above in 20 milliliters of aceticanhydride and milliliters of pyridine was allowed to stand overnight atroom temperature. After the addition of ice and extraction withchloroform, the extract was washed first with dilute hydrochloric acidand then water. The extract was then dried over sodium sulfate andconcentrated in vacuum to yield 2 8,3,B-diacetoxy-SB-cholestan-6-one,melting point 148 149 C. (from petroleum ether).

A solution of 1 gram of 2,8,3p-diacetoxy-5 8-cholestan- 6-one in 100milliliters of absolute methanol was treated with 0.5 gram of potassiumcarbonate and stirred overnight at room temperature. The resultingreaction mixture was poured into water and extracted with chloroform.After Workup of the extract, there was obtained25,3fl-dihydroxy-5l3-cholestan-6-one, melting point 167- 168 C. (fromacetonitrile and acetone).

'(D) Synthesis of 25,BB-isopropylidenedioxy- 5fl-cholestan-6-one Therewas added 7 grams of calcium chloride to a solution of 1.3 grams of2/3,3,B-dihydroxy-Sa-cholestan-fione in 70 milliliters of acetonecontaining 1 percent hydrochloric acid. The resulting reaction mixturewas stirred for 16 hours at room temperature and then poured into water.After extraction with ethyl acetate, washing the extract with water,dilute sodium bicarbonate solution and again with water, drying theextract and evaporation of the solvent, there was obtained25,3;3-isopropylidenedioxy-5/3-cholestan-6-one, melting point 171 C.(from acetonitrile).

EXAMPLE II.FROM 3fl-HYDROXY-A CHOLESTEN-6ONE (A) Synthesis of2fi-acetoxy-3/3-hydroxy-5tat-A"- cholesten-6-one A mixture of 11 gramsof 3,B-hydroxy-Sot-A' -cholesten- 6-one, grams of p-toluenesulfonicacid, and 250 milliliters of pyridine was stirred at room temperaturefor 24 hours and then poured into ice water. The precipitate Whichformed was filtered off and dissolved in methylene chloride. Theresulting solution was Washed with water, dried over sodium sulfate andevaporated to dryness. Upon recrystallization of the residue fromdiisopropyl ether, there was obtained 3B-tosyloxy-5u-A -cholesten-6-one, melting point l53-154 C.

A mixture of 4 grams of 3B-tosyloxy-5u-A -cholesten-6- one, 1 gram oflithium bromide, 1.5 grams of lithium carbonate, and 200 milliliters ofdimethylformamide was heated at 120 C. for 5 hours. After cooling, thereaction mixture was poured into ice water and weakly acidified withhydrochloric acid. The resulting precipitate was filtered off anddissolved in methylene chloride. The resulting solution was washed withwater, dried and concentrated to yield 5a-A -cholestadien-6-one.

The thus-produced 5u-A -cholestadien-G-one was dissolved in 250milliliters of acetic acid at 60 C. Thereafter, there was added insequence 3.9 milliliters of water, 3.1 grams of silver acetate, and 2grams of finely ground iodine. The resulting reaction mixture was heatedat 60 C. with vigorous stirring for 5 hours. After treating with anexcess of common salt and stirring for an additional 5 minutes, thereaction mixture was filtered. The deep red filtrate was concentrated todryness under vacuum. The residue was taken up in ether and the ethersolution was Washed with water, bicarbonate solution, and again withwater, and thein dried and concentrated. After recrystallization of theresidue from diisopropyl ether, there was obtained2/3-acetoxy-3/3-hydroxy-5a-A' -cholesten-6-one, melting point 215-2175C.

(B) Synthesis of 2 3,3fl-hydroXy-5ot-A cholesten-G-one A mixture of 1gram of 2/3-acetoxy-3fl-hydroxy-5u-A' cholesten-6-one and 1 gram ofpotassium carbonate in 100 milliliters of methanol was stirred at roomtemperature for 40 minutes. After pouring the resulting reaction mixtureinto water, the precipitate which had formed was filtered off anddissolved in methylene chloride. Workup of this'solution gave25,35-dihydroxy-5a-A' -cholesten-6- one, melting point 208-210 C. (fromacetone).

(C) Synthesis of 2,8,3/3-diacetoxyand 2 3,3,B-dihydroxy- 5fl-A'-cholesten-6-one 1 FROM 2B,3B-DIHYDROXY-5a-A -CHOLESTEN-G-ONE (a)Acid-catalyzed reaction.A mixture of 500 milligrams of26,3fl-dihydroxy-5a-A' -cholesten-6-one in 25 milliliters of ethanol and5 milliliters of 3 N hydrochloric acid was heated at boiling for hours.After cooling, the mixture Was poured into ice water and the precipitatewhich formed was separated and taken up in methylene chloride. Theorganic solution was washed with Water, dried with sodium sulfate andconcentrated in vacuum. On recrystallization of the residue fromdiisopropyl ether, there was obtained 2,8,3p-dihydroxy-A'-cholesten-6-one as an approximately equimolar mixture of the Soc-H- andS/R-H-isomers.

(b) Base-catalyzed reaction.A mixture of 500 milligrams of25,3,B-dihydroxy-5a-A -cholesten-6-one, 500 milligrams of potassiumhydroxide and 20 milliliters of methanol was heated under reflux for 2hours. After cooling, pouring the reaction mixture into ice water andworkup of the resulting precipitate as described above, there wasobtained 2,8,3,fi-dihydroxy-A' -cholesten-6-one as a mixture of theSa-H- and Sfl-H-isomers.

2) FROM 2/8-ACETOXY-3B-HYDROXY-5wA' CI-IOLESTEN-G-ONE (a) Acid-catalyzedreaction.A mixture of 1 gram of 2,8-acetoxy-3,B-hydroxy-Sa-A'-cholesten-6-one in 50 milliliters of ethanol and 10 milliliters of 3 Nhydrochloric acid was heated at boiling for 20 hours. After cooling andpouring the reaction mixture into ice water, the precipitate which hadformed was separated and taken up in methylene chloride. After workup ofthe organic solution, there was obtained 2B,3fl-dihydroxy-N-cholesten-6-one as a mixture of the Sa-H- and SH-H-isorners (b) Base-catalyzedreaction.A mixture of 500 milligrams of acetoxy-3,B-hydroxy-Sa-A'-cholesten-6-one and 500 milligrams of potassium hydroxide inmilliliters of methanol was heated under reflux for 4 hours. Aftercooling the reaction mixture and pouring it into ice water, theprecipitate which had formed was separated out and worked up asdescribed above to obtain 2,8,3flclihydroxy-A -cholesten-6-one as amixture of the Soc-H- and SB-H-isomers.

A solution of 1 gram of 2,8,3fl-dihydroxy-A' -cholesten-6-one-5-H-isomeric mixture produced as described above in 30 millilitersof acetic anhydride and 15 milliliters of pyridine was held at roomtemperature for 4 hours. The resulting reaction mixture was poured intoice water and extracted with methylene chloride. The organic extract waswashed with dilute sulfuric acid and water, dried and concentrated.After recrystallization from pentane, there was obtained2,8,3,8-diacetoxy-5fl-A -cholesten-6-one, melting point l66l68 C.

(4) PRODUCTION OF 2B,3fl-DIHYDROXY5,8A CHOLESTEN-G-ONE A mixture of 1gram of 2 8,3,8-diacetoxy-5fl-A' -cholesten-6-one, 1 gram of potassiumcarbonate, and 100 milliliters of methanol was stirred at roomtemperature for 40 minutes. The resulting reaction mixture was pouredinto water and the aqueous mixture was extracted with methylenechloride. The organic phase was washed with Water, dried, andconcentrated to obtain 2fl,3fl-dihydroxy- 3-A -cholesten-6-one, meltingpoint 207209 C. (from diisopropyl ether).

(D) Synthesis of 2,8,Zfl-isopropylidene-Sfl-A' cholesten-G-one Asolution of 400 milligrams of 2,8,3/3-(lll1Yd1'OXY-5ot- A-ch01esten-6-one in 100 millilters of acetone was cooled to 0 0.,treated with one drop of boron trifluoride etherate and held at 0 C. forminutes. The resulting reaction mixture was poured into water, extractedwith methylene chloride, and the methylene chloride phase was WashedWith Water, dried and concentrated to obtain2p,3fi-isopropylidenedioxy-SB-A' -cholesten-6-one, melting point163163.5 C. (from methanol).

(E) Synthesis of 25,35,14a-trihydroxy-5B-A cho1esten-6-one 1)INTRODUCTION OF THE la-HYDROXY GROUP FOLLOWED BY ISOMERIZATION Employingprocedures similar to those described in Example IA(3),2,8-acetoxy-3fl-hydroxy-A' -cholestem-6- one was acetylated to25,3,B-diacetoxy-5u-A -cholesten-6- one, melting point 196198 C. (frommethanol). Employing techniques similar to those described in Example IVbelow, this product was reacted with selenium dioxide in dioxane toproduce 2,8,3fl-diacetoxy-14oz-hydroxy-5u-A cholesten-6-one, meltingpoint 231-232 C. (from methanol). Employing procedures similar to thosedescribed in Example IC(2), the thus-obtained product was isomerizedwith potassium hydroxide in methanol. After Workup there was obtained 23,3 6,14u-trihydroxy-5B-A cholesten-6-one, melting point 207209 C. (fromether/ hexane).

In the manner described in Example IC( 3) above, the above-obtained218,35,l4a-trihydroxy-compound was reacted with acetic anhydride inpyridine to produce 2,6,3 8- diacetoxy 14oz hydroxy-5;8-A-cholesten-6-one, melting point 189-191 C. (from isopropyl ether).

(2) SIMULTANEOUS lite-HYDROXYLATION AND ISOMERIZATION A solution of 1gram of 2fl-acetoxy-3B-hydrOXy-Sa-A' cholesten-6-one in 100 millilitersof absolute dioxane was heated at 80 C. To this solution was added twol-gram portions of freshly sublimed selenium dioxide over a 30'- minuteperiod. The resulting mixture was heated an additional 2 /2 hours at 80C. with stirring. After filtration of the reaction mixture, the filtratewas concentrated under vacuum and mixed with water. The precipitatewhich formed was separated and dissolved in methylene chloride. Theresulting organic solution was washed with water, dried over sodiumsulfate and evaporated to obtain acetoXy-3B,14adihydroxy-Sfi-N-cholesten-G-one, melting point 260-261 C. (from diethylether).

EXAMPLE III.--FROM 318-ACETOXY-A ERGOSTADIEN-6-ONE (A) Synthesis of 23-acetoxy-3B-hydroxy-5a-A ergostadien-6-one A mixture of 11.7 grams of3fi-acetoxy-A -5a-ergostadien-6-one, 11.7 grams of potassium carbonateand 2 liters of methanol was heated at boiling for minutes. Theresulting reaction mixture, after cooling, was poured into water and theorganic phase was washed, dried, and concentrated.

The crude saponification product, in admixture with 200 milliliters ofpyridine and 13.5 grams of p-toluenesulfonyl chloride, was held at roomtemperature for 24 hours. After dilution of the reaction mixture withWater, the precipitate which had formed was separated off and dissolvedin methylene chloride. The organic solution was washed, dried andconcentrated to yield 3/3-tosyloxy- A -5a-ergostadien-6-one which, aftercrystallization from diisopropyl ether, melted at 148-149" C.

A mixture of 2.2 grams of 3fl-tosyloxy-A' -5a-ergostadien-6-one in 10milliliters of dimethylaniline was heated at 200C. for 20 minutes. Aftercooling, the reaction solution was poured into dilute sulfuric acid, andthe precipitate which formed was filtered ofl. by suction and taken upin chloroform. The organic solution was washed until neutral, dried andconcentrated to yield A -5ocergostatrien-6-one.

After dissolving the crude product in 130 milliliters of acetic acid at45 C., there was successively added 2.1 milliliters of water, 1.8 gramsof silver acetate and 1.09 grams of finely powdered iodine. Theresulting mixture was heated with vigorous stirring at 45 C. for 50minutes. After the addition of an excess of common salt, the reactionmixture Was stirred for an additional 5 minutes, filtered and thefiltrate concentrated to dryness in vacuum. The residue was purified bypreparative thin layer chromatography, and after recrystallization fromdiisopropyl ether, there was obtained 2/3-acetoxy-3fl-hydroxy-A' 5a-ergostadien-6-one, melting point 2082l0 C.

(B) Synthesis of 25,3,8-dihydroxyand 25,3B-diacetoxy- 5fl'A-ergostadien-6-one A solution of 2.1 grams of 2B-acetoxy-3fl-hydroxy-A'5a-ergostadien-6-one in 100 milliliters of ethanol and 20 milliliters of3 N hydrochloric acid was heated at boiling for 20 hours. After cooling,the reaction mixture was diluted with water and the precipitate whichformed was separated and taken up in methylene chloride. The organicsolution was washed with water, dried over sodium sulfate andconcentrated in vacuum to obtain 2 8,35- dihydroxy-A-5/3-ergostadien-6-one as an oil.

The diol was acetylated at room temperature for 16 hours by reactionwith 5 milliliters of pyridine and 2.5 milliliters of acetic anhydride.The resulting reaction mixture was diluted with water and theprecipitate which formed was filtered oif and dissolved in methylenechloride. After washing until neutral, the organic solution was driedand concentrated in vacuum to yield 218,3,8-diacetoxy-A"'-SB-ergQstadien-6-one, melting point 148-150 C. (from acetone/ hexane)(C) Synthesis of 2[3,3fl-diacetoxy-14x-hydroxy- 5,8-A ergostadien-6-oneA solution of 5.8 grams of 2,8-acetoxy-3,B-hydroxy-Sa- A'ergostadien-6-one in milliliters each of absolute pyridine and aceticanhydride was: allowed to stand at room temperature overnight and thenwas decomposed with ice water, and extracted with chloroform. Theextracts were washed until neutral and evaporated to yield2B,3fi-diacetoxy-Sa-A -ergostadien-6-one, melting point 195-196 C. (frommethanol).

A solution of 3 grams of 2 8,3/3-diacetoxy5a-A ergostadien-6-one in 120milliliters. of absolute dioxane was heated to 80 in an inertatmosphere. After the addition of 6.1 grams of selenium dioxide, thereaction mixture was stirred for 15 minutes, filtered, diluted withwater and extracted with ether. The extract was washed with water andthe solvent evaporated. The residue was chromatographed on grams ofalumina, using benzene containing 10 percent of ether as the elutingagent, to obtain 25,35 diacetoxy-l4a-hydroxy-5a-A' -ergostadien-6- one,melting point after recrystallization from isopropyl ether, 226-227 C.

A mixture of 1.3 grams of 2 8,3fl-diacetoxy-l4a-hydroxy- Soc-A-ergostadien-6-one, 60 milliliters of methanol, 5 milliliters of waterand 0.5 gram of potassium carbonate was heated at boiling overnight inan inert atmosphere. The reaction mixture was then diluted with waterand ex tracted with chloroform. The extract was washed until neutral,dried and evaporated. The crude reaction pro- 15 duct was reacted withacetic anhydride in pyridine according to the procedure described inExample 1C(3). After workup, the crude product was chromatographed on 30grams of alumina. Elution with benzene-ether (1: 1)

yielded 25,3[i-diacetoxy-14a-hydroxy-Sfl-A -ergostadien- 6-one, meltingpoint 202-203 C. (from methanol).

-In an alternative procedure a mixture of 1 gram of 2fiacetoxy-3fi-hydroxy-5a-A -ergostadien-6-one, 2 grams of selenium dioxideand 30 milliliters of absolute dioxane is stirred at room temperaturefor 24 hours. The reaction mixture was filtered and the filtrate wasstirred with 0.5 gram of deactivated Raney nickel. After filtration andevaporation, there was obtained 2/3-acetory-3fi,14a-dihydroxy-Sa-A-ergostadien-6-one, melting point 254-256 C. (decomp.) (fromacetonitrile).

A solution of 600 milligrams of 2,8-acetoxy-3fl,14adihydrOXy-SwA-ergostadien-6-one in 40 milliliters of methanol and 5 milliliters ofwater was treated with 250 milligrams of potassium carbonate accordingto the procedure described above. After workup, there was obtained2,8,3B-diacetoxy-14B-hydroxy-5/3-A' -ergostadien-6 one, which isidentical wit hthe product produced as described above.

(D) Synthesis of (22R),2;8,3[3,14a,22,25-pentahydroxy- 5fl-A'-cholesten-6-one (cedyson) A solution of 4 grams ofZfl,3B-diacetoxy-5a-A ergostadien-6-one (produced as described in part Cabove) in 750 milliliters of methylene chloride and 500 milliliters ofmethanol was treated at 70 C. over a 75-minute period with 10 millimolsof ozone which was supplied in an oxygen stream. After the addition ofmilliliters of trimethoxyphosphine, the mixture was stirred for 30minutes, then decomposed with water and extracted with ether. Processingof the other extract s afforded a crude product which was quicklychromatographed on alumina to obtain(S),Zfi,3,B-diacetoxy-ZO-formyl-Sot-A -pregnen- 6-one, melting point211-212 C. (from methylene chloride-ether) To a solution of ethylmagnesium bromide (prepared from 2 grams of magnesium and 6.4milliliters of ethyl bromide in 100 milliliters of ether), there wasadded dropwise a solution of 16 milliliters of2-methyl-2-tetrahydropyranyloxy-3-butyne in 100 milliliters oftetrahydrofuran. The reaction solution was stirred for minutes at roomtemperature and then added dropwise with stirring to a solution of 4.7grams of (20S),2fi,3fl-diacetoxy- 2O-formyl-5ot-A -pregnen-6-one in 200milliliters of tetrahydrofuran at 10 C. The temperature of the reactionmixture was allowed to rise to 0 C., whereupon the mixture wasdecomposed by the addition of ammonium chloride solution. Extractionwith ether afforded a crude product which was chromatographed on 200grams of alumina. The fractions obtained by elution with 2 liters ofbenzene-petroleum ether (1:1) were discarded. The

product was then eluted with chloroform containing 10 percent ofmethanol and again chromatographed on 140 grams of alumina. Afterremoval of undesired by-products, the (22R),213,3,8-diacetoxy-22-hydr0xy25 (tetrahydro pyran-Z-yloxy)-5a-A -cholesten-23-yn-6-one was elutedwith benzene and benzene containing 1 percent of ether. Melting point188 C. (from isopropyl ether).

A solution of 1 gram of (22R),2,8,3fl-diacetoxy-22-hydroxy-25-(tetrahydropyran 2 yloxy)-5ot-A -cholesten- 23-yn-6-one inmilliliters of methanol was hydrogenated in the presence of 200milligrams of prehydrogenated platinum until the uptake of 75milliliters of hydrogen. After workup there was obtained(22R),2fl,3;3-diacetoxy- 22-hydroxy-25-(tetrahydropyran 2 yloxy)-5a-A-cholesten-6-one, melting point 155156 C. (from isopropyl, ether).

A solution of 3 grams of (22R),2/3,3fl-diacetoxy-22-hydroxy-25-(tetrahydropyran 2 yloxy)-5a-A' -cholesten- 6-one in 150milliliters of absolute dioxane was stirred with 6 grams of seleniumdioxide at 20 C. for 15 hours.

The suspension was filtered, and 1 gram of deactivated Raney nickel wasadded to the filtrate. After stirring for 30 minutes and filtration, thesolution was diluted with chloroform, washed with water and evaporated.Recrystallization of the residue from ether afforded (22R),2,B,3;3-diacetoxy 14oc,22 dihydroxy-25-(tetrahydropyran-Z- yloxy)-5a-A-cholesten-6-one, melting point 194-195 C.

A solution of 1 gram of (22R),2B,3B-diacetoxy-14u,22-dihydroxy-25-(tetrahydropyran 2 yloxy)-5a-A -cholesten-6-one and 200milligrams of potassium carbonate in 20 milliliters of methanol washeated to reflux for 2 hours. The reaction mixture was diluted with 200milliliters of ethyl acetate, washed with saturated brine, dried andevaporated. The residue was dissolved in 16 milliliters of methanol, andallowed to stand with 4 milliliters of 2 N hydrochloric acid for 15minutes at room temperature. The mixture was then neutralized with 8milliliters of 1 N sodium hydroxide and, after the addition of ethanol,evaporated to dryness. The residue was dissolved in tetrahydrofuran andthe resulting solution was filtered and evaporated. Recrystallizationfrom methyl ethyl ketone afforded(22R),2/3,3,8,14a22,25-pentahydroxy-5,8-A -cholesten-6-one, meltingpoint 233 C. (decomp.). Melting point after further recrystallizationfrom methanol-acetone, 241 C. (decomp.).

(E) Synthesis of 3 fl-acetoxy-22-hydroxy-25-(tetrahydropyran-Z-yloxy)-5a-A -cholesten-23 -yn-6-one Employing procedures similar to thosedescribed above, 3{i-acetoxy-A' -5a-orgostadien-6-one was subjected toozonolysis to produce 3[3-acetoxy-20-formyl-5a-N-pregnen-6-one.

To an ethyl magnesium bromide solution [produced from 244 milligrams ofmagnesium and 0.84 milliliter of ethyl bromide in 15 milliliters ofether], there was added dropwise a solution of 1.93 milliliters of2-methyl- 2-tetra-hydropyranyloxy-3-butyne in 10 milliliters oftetrahydrofuran, and the resulting mixture was stirred for one hour atroom temperature. The resulting solution was cooled to 0-5 C. and therewas added a solution of 386.5 milligrams of 3,8-acetoxy-20-formyl-5a-A-pregnen-6-one in 10 milliliters of tetrahydrofuran. The resultingmixture was stirred for 45 minutes and then mixed with saturatedammonium chloride solution. After taking the product up in ether, it waswashed with saturated salt solution, dried and evaporated. Afterchromatographing on silica gel, there was obtained3fi-acetoxy-22-hydroxy- 25-(tetrahydropyran-Z-yloxy)-5a Acholesten-23-yn- 6-0ne, melting point 175l78 C. (from hexane/ether).

EXAMPLE IV.FROM METHYL 3,3-ETHYLENE- DIOXY-A -PREGNENE-ZO-CARBOXYLATE(A) Synthesis of methyl 3,3-ethylenedioxy-5,6-oxidopregnene-ZO-carboxylate To a mixture of 331 grams of methyl3,3-ethylenedioxy- A -pregnene-20-carboxylate [K. Morita, Chem. Abs.,54, 4679 (1960)], grams of potassiumacetate, 166 grams of sodiumsulfate, and 3300 milliliters of methylene chloride, there was addeddropwise under ice cooling 275 milliliters of 40 percent peracetic acid.The resulting reaction mixture was stirred at 22 C. for 2 hours, treatedwith water and diluted with methylene chloride. The methylene chloridephase was separated, washed with sodium carbonate solution and water,dried over sodium sulfate and evaporated in vacuum to yield the desired5,6-oxido-compound as an isomeric mixture.

(B) Synthesis of SB-H-compounds via 5,6 epoxides (1) SYNTHESIS OF METHYL213,3;3-DIHYDROXY-5fififi- OXIDOPREGNANEQO-CARBOXYLATE The epoxidemixture as described in A above was dissolved in 2500 milliliters oftetrahydrofuran, treated at 05 C. with 690 milliliters of 3 N perchloricacid and allowed to stand at 5 C. for 16 hours. The resulting solutionwas stirred into 30 liters of ice Water, neutralized and 17 theprecipitated diol was filtered otf by suction, washed and dried. Afterrecrystallization from acetone, there was obtained methyl5a,6,8-dihydroxypregnan-3-one-20-carboxylate, melting point 233-235 C.

To a solution of 10 grams of the SaGB-diol in 128 milliliters oftetrahydrofuran there was added dropwise over 8 minutes with ice coolinga solution of 1.365 milliliters of bromine in 15 milliliters of glacialacetic acid. After stirring for an additional 5 minutes the reactionsolution was poured into ice water containing sodium acetate and thenextracted with methylene chloride. The methylene chloride solution waswashed until neutral, evaporated in vacuum at 30 C. and the residue wastriturated with isopropyl ether to yield methyl2a-bromo-5ix,6B-dihydroxypregnan- 3-one-20-carboxylate.

To a mixture of 8.9 grams of the thus-obtained 2a-bromo-compound in 80milliliters of dry tetrahydrofuran, there was added at -5 C. a solutionof 9.6 grams of lithium tri(tert.-butoxy)aluminum hydride in 50milliliters of tetrahydrofuran. The resulting mixture was stirred into asulfuric acid/ice water mixture, extracted with acetic ester, washeduntil neutral and evaporated in vacuum. Upon recrystallization fromisopropyl ether and then from acetone there was obtained methyl2a-bromo- 3 ,8,5a,6fi-trihydroXypregnane-ZO-carboxylate, melting point217-218" C. (dec.).

A solution of 8.5 grams of the thus-obtained triol in 85 milliliters ofglacial acetic acid was treated with 17 milliliters of acetic anhydrideand 850 milligrams of p-toluenesulfonic acid and then allowed to standat room temperature for 48 hours. The resulting solution was stirredinto ice water and the resulting precipitate was filtered off bysuction, washed with water and dried. After recrystallization fromisopropyl ether, there was obtained methyl2a-bromo-3fi,5a,6fi-triacetoxypregmane-20-carboxylate, melting point2112l3 C. (dec.).

A solution of 7.1 grams of the triacetate in 145 milliliters of glacialacetic acid was heated under reflux for 22 hours with 5 grams of silveracetate and 3 milliliters of water. The precipitate was filtered off bysuction, and the filtrate was poured into ice water. The reactionproduct which precipitated was filtered off by suction, washed untilneutral and dried. After chromatographing on silica gel andrecrystallization from acetone/hexane, there was obtained methyl2133p,5u,6B-tetraacetoxypregnane-ZO-carboxylate, melting point 202203 C.

A solution of 15.74 grams of tetraacetate in 315 milliliters of methanoland 79 milliliters of water was refluxed for 2 hours with 11.8 grams ofpotassium hydroxide and then neutralized with acetic acid. After vacuumdistillation to remove the methanol, the residue was treated with 200milliliters of water. The reaction product which precipitated wasfiltered off by suction, washed with water and dried. The crudecarboxylic acid thus obtained was allowed to stand at room temperaturefor one hour in 200 milliliters of methylene chloride and 200milliliters of etheric diazomethane solution (manufactured from 30 gramsof nitrosomethylurea). After evaporation in vacuum, chromatography ofthe residue on silica gel and recrystallization from acetone/ hexane,there was obtained methyl25,3,8-dihydroxy-5,6fl-oxidopregnane-20-carboxylate, melting point185.5-186 C.

2) SYNTHESIS OF METHYL 23,35-ISOPHOPYLIDENE-DIOXY-SfiB-OXIDOPREGNANE-20-CARBOXYLATE A mixture of 300 milligrams ofthe tetraacetate produced as described above in 6 milliliters of a 10percent methanolic potassium hydroxide solution was allowed to stand atroom temperature for 16 hours. After acidification with 1 N hydrochloricacid, the solution was diluted with ethyl acetate, washed until neutraland evaporated. The residue was admixed with 30 milliliters of ethericdiazomethane solution (manufactured from 2 grams of nitrosomethylurea)and allowed to stand for 2 hours. The resulting solution was evaporatedunder vacuum and the residue was purified by preparative thin layerchromatography to obtain methyl 213,3B,68-trihydroxy-5a-acetoxypregnane-ZO-carboxylate, melting point 220-221.5C.

A mixture of 2.55 grams of the trihydroxy-m-onoacetoxy compound, 0.4milliliter of boron trifluoride etherate, and milliliters of dry acetonewas allowed to stand at room temperature for 30 minutes. After theaddition of 2 milliliters of pyridine, the reaction mixture wasevaporated under vacuum and the residue was precipitated with ice water.After filtering off the precipitate by suction, it was dried and thenrecrystallized fromacetone/hexane to yield methyl2B,3/3-isopropylidenedioxy-5a-acetoxy-6B-hydroxypregnane-20-carboxylate, melting point 192.5- 193 C.

A mixture of 600 milligrams of this product, 48 milliliters of methanol,12 milliliters of water, and 1.8 grams of potassium hydroxide was heatedunder reflux for 3% hours. The mixture was then stirred into ice water,acidi tied with hydrochloric acid, and the resulting precipitate wasfiltered off by suction, washed until neutral and dried. The crude acidwas dissolved in 5 milliliters andtetrahydrofuran and allowed to standfor 2 hours with 30 milliliters of etheric diazomethane solution. Theresulting solution was evaporated under vacuum and the residue wasfractionated by preparative thin layer chromatography to yield methyl2B,3fl-isoproplyidenedioxy-S,6fi-oxidopregnane-ZO-carboxylate, meltingpoint 149.5- C, and methyl25,3B-isopropylidenedioxy-5a,6,8-dihydroxypregnane-20-carboxylate,melting point 266267 C (3) SYNTHESIS OF METHYL 2,B,3B-ISOPROPYLIDENE-DIOXY-5,6a-OXIDOPREGNANE-ZO-CARBOXYLATE A mixture of 200 milligrams ofthe Sa,6B-diol produced as described above, 5 milliliters of pyridineand 0.5 milliliter of methanesulfonic acid chloride was stirred at 5 C.for 16 hours. The resulting mixture was poured into ice water, filteredby suction and dried. The crude 6-mesylate in admixture with 10milliliters of pyridine, l0 milliliters of water, and 3 grams of sodiumbicarbonate was heated under reflux for 30- minutes. The resultingmixture was stirred into Water and extracted with methylene chloride.The methylene chloride solution was washed with dilute hydrochloric acidand water and then evaporated. After recrystallization from acetone,there was otbained methyl2,8,3fl-isopropylidenedioxy-5,6uoxidoprognane-ZO-carboxylate, meltingpoint l99201 C.

(4) SYNTHESIS OF METHYL 2B,3BDIHYDROXY- AND 213,3 3 DIACETOXY 5BPREGNAN-G-ONE-ZO-CARBOX- YLATES (a) From methyl25,3fl-dihydroxy-S,6B-oxido-pregnane-20-carboxylate.A mixture of 100milligrams of methyl 213,3,8 dihydroxy 5,613oxidopregnane-ZO-carboxylate, l0 milliliters of benzene, and 0.1milliliter of boron trifluoride etherate was stirred at room temperaturefor 20 hours. After the addition of 0.5 milliliter of pyridine, themixture was diluted with ethyl acetate, washed in sequence with water, 1N hydrochloric acid, and again with water, dried and evapoarted. Fromthe residue there was isolated by preparative thin layer chromatographymethyl 2,8,35-dihydroxy'5fl-pregnan-G- one-20-carboxylate, which afterrecrystallization from isopropyl ether/methylene chloride, melted at181.5- 183 C.

(b) From methyl 2 8,3/3isopropylidenedioxy-5,6,B-oxidopregnane-20-carboxylate.A mixture of 100 milligrams of methyl 25,313isopropylidenedioxy 5,6fl-oxidopregnane-O-carboxylate, 5 milliliters ofacetone and 0.2 milliliter of boron trifluoride etherate was stirred atroom temperature for 1 hour and then treated with 0.5 milliliter ofpyridine and evaporated under vacuum. The residue was heated on a steambath for 2 hours in admixture with 10 milliilters of 61 percent aceticacid and 1 drop of 2 N sulfuric acid. The resulting mixture was stirredinto water and extracted with chloroform. The extract was washed withwater, evaporated and the residue was recrystallized from isopropylether to yield methyl 2,8,35-

washed until neutral, concentrated and recrystallized from isopropylether to yield methyl 25,3fi-diacetoxy-5B-pregnan-6-one-20-carboxylate,melting point 176.5-177.5 C.

(5) SYNTHESIS OF METHYL 25,3fi-ISOPROPLIDENE-DIOXY-5/3-PREGNAN-GONE-20-CARBOXYLATE (a) From methyl 2 3,35isopropylidenedioxy 5,604- oxidopregnane-Z-carboxylate.-A mixture of 200milligrams of methyl25,3[3-isopropylidenedioxy-5,6a-oxidopregnane-ZO-carboxylate, 10milliliters of benzene, and 0.2 milliliter of boron trifiuoride etheratewas stirred for hours at room temperature. After workup as described inpart (4) (a) above, there was recovered methyl 25,35-isopropylidenedioxy 5B pregnan 6 one-20-carboxylate, melting point196.5-198 C. (from isopropyl ether).

(b) From methyl 25,3,8-dihydroxy-Sfl-pregnan-6-one- 20-carboxylate.-Amixture of 150 milligrams of methyl 2,8,33 dihydroxy 5,6 pregnan 6one-20-carboxylate, 10 milliliters of acetone, and 0.03 milliliter ofboron fluoride ethereate was allowed to stand at room temperature for 30minutes. After Workup as described above, there was obtained methyl2,8,3,8-isopropylidenedioxy-5,8- pregnan-6-0ne-20-carboxylate identicalto that produced in part (a) above.

(C) Synthesis of Sfl-H-compounds via isomerization of 5u-H-compounds 1)SYNTHESIS OF METHYL (S),2B,3fl-DIACETOXY-5a- PREGNAN-6ONE20-CARBOXYLATEAn epoxide mixture produced in the manner described in A above wasdissolved in 2500 milliliters of tetrahydrofuran, treated with 690milliliters of 3 N perchloric acid and heated under reflux for 3.5hours. The resulting solution was stirred into liters of ice water,neutralized and the precipitated dione filtered off by suction. Afterwashing, drying, and recrystallization from ethyl acetate, there wasobtained methyl (20S),5a-pregnane-3,6-dione- 20-carboxylate, meltingpoint 2122l4 C.

To a mixture of 37.45 grams of the 3,6-dione in 800 milliliters oftetrahydrofuran, there was added dropwise with ice cooling a solution of5.33 milliliters of bromine and 4.9 grams of potassium acetate inmilliliters of glacial acetic acid. The resulting reaction solution waspoured into ice water containing sodium acetate. The precipitate whichformed was filtered off by suction and recrystallized from methanol toyield methyl (20$),2abromo 50c pregnane-3,6-dione-20-carboxylate,melting point 161-162" C. (dec.).

A solution of 28 grams of the 2a-bromo-3,6-dione in 240 milliliters oftetrahydrofuran was diluted at 05 C. with a solution of 33.8 grams oflithium tri(tert.-butoxy) aluminum hydride in 160 milliliters oftetrahydrofuran. The resulting mixture was stirred into a sulfuricacid-ice water mixture and the precipitate which formed was filtered offby suction and recrystallized from ethyl acetate to yield methyl(20S),2a-bromo-3 8-hydroxy-5u-pregnan- 6-one-20-carboxylate, meltingpoint 211-212 C.

A mixture of 19.4 grams of the resulting alcohol in 80 milliliters ofpyridine and 40 milliliters of acetic anhydride was allowed to stand atroom temperature for 20 hours. The resulting mixture was stirred intoice water and the precipitate which formed was filtered off by suctionand recrystallized from acetone/hexane to yield methyl (20S),2u bromo5tat-pregnan-6-one-20-carboxylate, melting point 196-197" C.

A mixture of 81.2 grams of the product acetate, 800 milliliters ofglacial acetic acid, 16.2 milliliters of water and 50 grams of silveracetate was heated under reflux for 20 hours. The precipitate whichformed was filtered off by suction and the filtrate was stirred into icewater. The resulting precipitate was filtered off by suction, washeduntil neutral, and dried. After recrystallization from methanol, therewas obtained 58.6 grams of methyl(20S),2,8,35-diacetoxy-pregnan-6-one-20-carboxylate as a mixture of 5wand SB-isomers. After fractional crystallization from methylenechloride-isopropyl ether and methylene chloride-methanol, there wasrecovered the 504- isomer, melting point 222.5224 C., and the SB-isomer.melting point 176.5-177.5 C-

(2) SYNTHESIS OF METHYL 25,3 3-DIACETOXY-5d-N-PREGNAN-G-ONEZO-CARBOXYLATE A mixture of 29.3 grams of the mixture ofSoc-H- and 5,8-H-isomers produced as described above in 500 millilitersof glacial acetic acid was treated dropwise with 3.3 grams of bromine inglacial acetic acid and the resulting mixture was stirred at 50 C. for 2hours. The reaction mixture was then stirred into an ice/potassiumacetate solution and the precipitate which formed was filtered off bysuction, washed until neutral, and dried. After recrystallization fromacetone/hexane, there was otbained methyl(20S),2,8-3fl-diacetoxy-7a-brOmO-Sa-pregnan 6 one-20- carboxylate,metling point 152-153 C.

A mixture of 38 grams of the 7a-bromo compound, 10.3 grams of lithiumcarbonate, 6.2 grams of lithium bromide, and 380 milliliters ofdimethylformamide was heated at -125 C. for 4.5 hours under a nitrogenatmosphere. After filtration to remove undissolved lithium salts, thefiltrate was stirred into ice water. The precipitate which formed wasfiltered off by suction, dried and chromatographed on silica gel. Afterrecrystallization from isopropyl ether/methylene chloride, there wasobtained methyl (20S),2 3,3fi-diacetoxy-Sa-N-pregnen-6-one-20-carboxylate, melting point 196 C.

(3) SYNTHESIS OF METHYL 2B,35-DIHYDROXY- and 25,318-DIACETOXY-5B-A7-PREGNEN-6-ONE-2O-CARBOXYLATE A solution of 500milligrams of methyl 2,8,3B-diacetoXy-5u-A-pregnen-6-one-20-carboxylate, 20 milliliters of ethanol and 1.5milliliters of 3 N hydrochloric acid was heated under reflux for 20hours and worked up as described above. The resulting mixture of 5aand55-H- isomers was then acetylated as described above to yield methyl(20S),2,B,3[3 diacetoxy-5,8-A' -pregnen-6-one-20- carboxylate, meltingpoint 194.5195.5 C. Hydrolysis of this product as previously describedyields the corresponding methyl 2/3,3,8-dihydroxy-SB-H-isomer, meltingpoint 224-226 C. (from acetone/ hexane).

(4) SYNTHESIS OF METHYL 25,35,14a-TRIHYDROXY- AND 2B,33-DIACETOXY-1eta-HYDROXY-EB-N-PREGNEN- G-One-ZO-CARBOXYLATE A mixture of1.5 grams of methyl (20S),2fi,-3B-diacetoxy-Su-A'-pregnen-6-one-20-carboxylate, 1.5 grams of selonium dioxide and 107milliliters of dioxane was stirred at 90 C. for 30 minutes. Afterfiltering off the insoluble selenium, the filtrate was stirred into icewater. The precipitate which formed was filtered off by suction, washeduntil neutral and dried. After recrystallization from methanol, therewas obtained methyl (20S),2B,3fl-diacetoxy-14whydroxy-5a-N-pregnen-G-one20 carboxylate,

melting point 248-2495 C.

A 300-milligram portion of the resulting product was heated under refluxin 10 milliliters of methanol and 0.5 gram of potassium hydroxide for 1hour and then Worked up as described above. After recrystallization fromacetone, there was obtained methyl (20S),2[3,3B,14a-trihydroxy-5B-A'-pregnen-6-one-20-carboxylate, melting point 238-240" C.

Employing procedures similar to those described above, 30 milligrams ofthe 2;3,35,14u-trihydroxy compound were acetylated with 1 milliliter ofpyridine in 0.5 milliliter of acetic anhydride. After recrystallizationfrom acetone/hexane, there was obtained methyl(20S),2B,3,3-diacetoxy-14ahydroxy-5B-A -pregnen-6-one 20 carboxylate,melting point 241-242 C.

() SYNTHESIS OF (22R),25,3B,14a,22,25 PENTAHY-DROXY-Eifi-N-CHOLESTEN-6-ONE (ECDYSON) A mixture of grams of methyl(S),2,3,3p-diacetoxy-Sa-A' -pregneu-6-one-20-carboxylate, 12 grams ofanhydrous lithium iodide, and 100 milliliters of lutidine was heatedunder reflux for 2 hours. The resulting reaction mixture was poured intoice water, acidified with hydrochloric acid and saturated with sodiumchloride. The insoluble reaction product was filtered olf by suction,dissolved in methylene chloride and chromatographed twice on silica gel.On recrystallization from acetone/hexane, there was obtained (20S),23,SB-diacetoxy-SB-A -pregnen- 6one-20-carboxylic acid, melting point245-247 C. There was also recovered methyl (20R),2,8-3 3-diacetoxy- 5p-A-pregnen-6-one-2O-carboxylic acid, melting point 205.5-208 C. (fromacetone/hexane).

A mixture of 1.9 grams of the (20S),20-carboxylic acid, 38 millilitersof absolute tetrahydrofuran, and 10 grams of carbonylidimidazole washeated for 20 minutes under reflux. The resulting reaction solution waspoured into ice water, acidified with hydrochloric acid, and saturatedwith sodium chloride. The insoluble imidazolide was separated and dried.A solution of a Z-gram portion of the imidazolide in 40 milliliters oftetrahydrofuran was treated with 2 grams of lithiumtrl-(tert.-butoxy)aluminum hydride and then stirred at room temperaturefor 1 hour. The resulting mixture was then stirred into ice water,acidified with hydrochloric acid and, after buffering with sodiumethylate, extracted with methylene chloride. After distillation of thesolevnt, chromatographing on silica gel, and crystallization fromacetone/hexane, there was obtained (20S),2;8,3 3diacetoxy-20-formyl-SB-N- pregnen-6-one, melting point 200-202 C.

To an ethyl magnesium bromide solution (produced from 488 milligrams ofmagnesium and 1.68 milliliters of ethyl bromide in milliliters ofether), there was added 3.86 milliliters of2-methyl-Z-tetrahydropyranyloxy- S-butyne in 20 milliliters oftetrahydrofuran dropwise. After stirring for minutes, the Grignardsolution was added to an ice-cooled solution of 820 milligrams of the20-formyl compound produced as described above in 20 milliliters oftetrahydrofuran and then stirred for 5 minutes. The reaction mixture wastreated with saturated ammonium chloride solution and the reactionproduct was taken up in ether, washed with saturated salt solution,dried and evaporated. After chromatographing on silica gel, there wasobtained (22R),2B,3fl-diacetoxy-22-hydroxy 25tetahydropyranyloxy--N-cholesten-Z3-yn- 6-one, melting point 175-l78 C.(from hexane/ether). The (22S)-isomer (melting point 172-l73 C.) wasalso obtained.

To a solution of 227 milligrams of this product in 10 milliliters ofmethanol, there was added milliliters of platinum dioxide and theresulting mixture was hydrogenated until hydrogen uptake ceased. Afterfiltration of the catalyst and evaporation of the solvent under vacuum,the residue was crystallized from acetone/hexane to yield (22R),2e,3p,22trihydroxy 25 -tetrahydropyranyloxy- 5B-A' -cholesten-23-yn-6-one,melting point l47-150 C.

A solution of 100 milligrams of the thus-produced trio] in 2 millilitersof dioxane was treated with 100 milligrams of selenium dioxide andheated for 1 hour at 90 C. The resulting reaction mixture was subjectedto preparative thin layer chromatography and after crystallization fromtetrahydrofuran/pentane, there was obtained (22R),2/3, 3,8,14a,22,25pentahydroxy 5,8 A cholesten-6-one (ecdyson), melting point 232-233 C.

Employing the (22S)-isomer isolated after the Grignard reaction, therewas produced in a similar manner(22S),2;8,3fi,14a,22,25-pentahydroxy-SB-N-cholesten- 6-one (isoecdyson),melting point 227230 C. (from acetone).

22 EXAMPLE V.-FROM 3,3-ETHYLENEDIOXY-20- HYDROXYMETHYL-M-PREGNENEmploying procedures similar to those described in Example IVA,3,3-ethylenedioxy-20-hydroxymethyl-A pregnen was reacted with peraceticacid to produce the corresponding 5,6-epoxide, which was converted to20- hydroxymethyl-Sa-pregnane-3,6-dione (melting point 180 181 C.) bytreatment with perchloric acid in the manner described in ExampleIVC(1).

Employing the techniques described in Example IVC(l), the dione wasreacted with bromine to produce 2a bromo 20hydroxymethyl-5u-pregnane-3,6-dione, the ZOL-bl'OIIlO compound wasreduced with lithium tri (tert.-butoxy)aluminum hydride to produce2u-bromo- 3/3 hydroxy 20-hydroxyrnethyl-5a-pregnan-6-one, followed byacetylation to 3,B-acetoxy-20-acetoxymethyl-2ubromo-5a-pregnan-6-one(melting point 208-209 C.), and then reacted with silver acetate toproduce 218,3;8-diacetoxy-ZO-acetoxymethylpregnau-6-one as a mixture ofthe Su-H- and Sfl-H-isomers.

Employing procedures similar to those described in Example IVC(2), theisomeric mixture was brominated to form2/3,3B-diacetoxy-20-acetoxymethyl-7a-br0mo-5apregnan-6-one (meltingpoint 147-l48 C.) which was dehydrobrominated to form2,8,3B-diacetoxy-20-acetoxymethyl 5a A pregnen 6-one (melting point208.5- 209 C.).

The triacetate was reacted with selenium dioxide in the manner similarto that described in Example IVC(4) to produce 213,313 diacetoxy 20acetoxymethyl-14ot-hydroxy-5a-A -pregnen-6-one, melting point 253-254 C.

A solution of 550 milligrams of 2 8,3;3diacetoxy-20-acetoxymethyl-14ahydroxy-5a-A --prcgnen-6-one in 27.5 milliliters of 1percent potassium hydroxide in methanol was heated at boiling for 30minutes. The reaction mixture was then processed in a manner similar tothe procedure described in Example 10 to obtain 23,3p,14a-trihydroxy-20-hydroxymethyl-5B-A -pregnen-6-one, melting point255-257 C. (from tetrahydrofuran-ethyl acetate).

A solution of 200 milligrams of 2;S,3p,l4a-trihydroxy-2O-hydroxymethyI-Sfl-A' -pregnen-6-one in 50 milliliters of acetone wastreated with 0.2 milliliter of boron trifluoride etherate and processedas described in Example IID. There was obtained 23,3B-isopropylidenedioxy-14a-hydroxy20-hydroxymethyl-Sfl-N-pregnen-6-one, melting point 240-241 C. (fromacetone/hexane).

EXAMPLE VI.FROM 3u-HYDROXY-20,20-ETH- YLEN-EDIOXYPREGNAN-6-ONE3a-hydroxy-20,20-ethylenedioxypregnan-6-one was oxidized in known mannerto 20,20-ethylenedioxypregnane- 3,6-dione. Employing techniquesdescribed in Example IVC, the 3,6-dione was brominated to form 2a-bromo-20,ZO-ethylenedioxypregnane-3,6-dione, the 2u-bromocompound was reducedwith lithium tri(tert.-butoxy) aluminum hydride to form2u-bromo-3,8-hydroxy-20,20= ethylenedioxypregnan-6-one, the alcohol wasconverted to the corresponding 3/3-acetate, and the 2a-bromo-3fiacetoxy20,20 ethylenedioxy 5a-pregnan-6-one was reacted with silver acetate toproduce 25,3;9-diacetoxy- 20,20-ethylenedioxypregnan-6-one as a mixtureof the 50:- H- and 5/3H-isomers.

Employing procedures similar to those described in Example IVC, theisomeric mixture was brominated to form 2 8,3 8 diacetoxy7m-bromo-20,20-ethylenedioxy- 5a-pregnan-6-one, followed bydehydrobromination to 6 diacetoxy 20,20 ethylenedioxy-5a-A -pregnen--one.

Acidic ketal cleavage in known manner lead to 25,3/3- diacetoxy-5a-A-pregnene-6,20-dione. This dione was then reacted with2-methyl-2-tetrahydropyranyloxy-S-bromopentane, employing the knownWittig-reaction techniques, to produce213,3B-diacetoxy-25-te'trahydropyranyloxy-5a- M -cholestadien-6-one.After selective epoxidation of the A -double bond, hydrolysis of theepoxide to the 23 20,22-diol and l4a-hydroxylation with seleniumdioxide, there was obtained 25,3;3-diacetoxy-14a,20,22,25-tetrahydroxy-Sa-A -chloesten-6-one.

A solution of 500 milligrams of 2B,3fl-diacetoxy-14a,-20,22,25-tetrahydroxy-A -cholesten-6-one and 250 milligrams of potassiumcarbonate in 100 milliliters of methanol was heated at boiling for 50minutes. The reaction mixture was then neutralized with acetic acid andevaporated to dryness in vacuo. Isolation and purification of thereaction product was accomplished by preparative layer chromatography onsilica gel using chloroformmethanol. There was obtained2,6335,14a,20,22,25-hexahydroxy-Sfl-A -cholesten-6-one, melting point237.5-239.5 C.

We claim:

1. A compound of the formula:

wherein R and R independently, are members selected from the groupconsisting of hydroxy and a radical derived from an aliphatic carboxylicacid of up to 11 carbons by removal of the hydroxygen of a carboxylgroup and R and R when taken together and R is in the ,8- configurationare lower alkylenedioxy; Z is a member selected from the groupconsisting of hydrogen and lower alkyl; and R is hydrogen or hydroxy.

2. A compound as in claim 1 wherein Z is methyl.

3. A compound as in claim 2 wherein R and R are both fl-hydroxy.

4. A compound as in claim 2 wherein R and R are both ,B-acetoxy.

5. A compound as in claim 4 wherein R and R when taken together areisopropylenedioxy.

6. A compound as in claim 1 wherein R is hydrogen.

7. A process for producing a compound of the formula:

wherein R and R independently, are members selected from the groupconsisting of hydroxy and, a radical derived from an aliphaticcarboxylic acid of up to 11 carbons by removal of the hydrogen of acarboxyl group and R and R when taken together and R is in the ,B-con-24 figuration are lower alkylenedioxy;.comprising reacting a compound ofthe formula:

l l AM/ l0 Rzlwv 15 wherein R and R are as above, with a carbonyldiimidazole and thereafter reacting the thus produced imidazolide with alithium tri-(lower alkoxy)-aluminum hydride.

8. The process for producing a compound of the formula:

H ?HCHO HM) Y k/I wherein R and R independently, are members selectedfrom the group consisting of hydroxy and, a radical de- 5 rived from analiphatic carboxylic acid of up to 11 carbons by removal of the hydrogenof a carboxyl group and; R and R when taken together and R is in the ,8-configuration are lower alkylenedioxy; comprising reacting a compound ofthe formula:

HaCCCOOH mo I H C a Q R R2 I wherein R and R are as above, with acarbonyl diimidazole and thereafter reacting the thus produced imidazolewith a lithium tri-(lower alkoxy)-aluminu r hydride. 9. The process ofclaim 8 wherein the tri-(lower alkoxy)-aluminum hydride is lithiumtri(t-butoxy) aluminum hydride.

10. The process for producing a compound of the formula:

HaC-CCOOH HaC I HaG Q R1 1 B5 A a l H ll wherein R and R independently,are members selected from the group consisting of hydroxy and a radicalderived from an aliphatic carboxylic acid of up to 11 carbons by removalof the hydrogen of a carboxyl group;

wherein R R R and A are as above, and Z is lower alkyl; with a mixtureof lithium iodide and lutidine.

References Cited 5 UNITED STATES PATENTS 3,354,152 11/1967 Edwards eta1. 260239.55 3,378,549 4/1968 Edwards et al. 260-23955 0 ELBERT L.ROBERTS, Primary Examiner US. Cl. X.R.

